Until the mid-1980s, the accepted treatment for coronary atherosclerosis, i.e., narrowing of the coronary artery(ies) was coronary by-pass surgery. While being quite effective and having evolved to a relatively high degree of safety for such an invasive procedure, by-pass surgery still involves potentially serious complications and generally results in an extended recovery period.
With the advent of percutaneous transluminal coronary angioplasty (PTCA) in 1977, the scene changed dramatically. Using catheter techniques originally developed for heart exploration, inflatable balloons were deployed to re-open occluded regions in arteries. The procedure was relatively non-invasive, took a short time compared to by-pass surgery and recovery time was minimal. However, PTCA brought with it its own problems including vasospasm, elastic recoil of the stretched arterial wall and restenosis, the re-clogging of the treated artery due to neointimal hyperplasia in the vicinity of the procedure, any of which could undo much of what was accomplished.
The next improvement, advanced in the mid-1980s, was the use of a stent to maintain a luminal diameter that had been re-established using PTCA. This for all intents and purposes put an end to vasospasm and elastic recoil but did not resolve the issue of restenosis. That is, prior to the introduction of stents, restenosis occurred in about 30 to 50% of patients undergoing PTCA. Stenting reduced this to about 15 to 20%, a substantial improvement but still more than desirable.
In 2003, the drug-eluting stent (DES) was introduced. The drugs initially used with DESs were cytostatic compounds, that is, compounds that curtailed the proliferation of cells that fostered restenosis. The occurrence of restenosis was reduced to about 5 to 7%, a relatively acceptable figure. However, the use of DESs engendered yet another complication, late stent thrombosis, the forming of blood clots some time after the stent was in place. It was hypothesized that the formation of blood clots was most likely due to delayed healing, a side-effect of the use of cytostatic drugs.
The physiopathology of restenosis involves early injury to smooth muscle cells (SMCs), de-endothelialization and thrombus deposition. Over time, this leads to SMC proliferation and migration and extra-cellular matrix deposition. There is an increasing body of evidence suggesting that inflammation plays a pivotal role in linking early vascular injury with neointimal growth and eventual lumen compromise, i.e., restenosis. Further, it has been observed that, when stents are used, the inflammatory state if often more intense and prolonged, exacerbating the situation.
Inflammation is, of course, a normal response to injury and is a necessary element of the healing process. Chronic inflammation, however, can be detrimental to healing in that the continuous recruitment of monocytes, lymphocytes and neutrophils leads to a constant generation of inflammatory cytokines along with reactive oxygen species and enzymes generated by inflammatory cells to remove foreign bodies or damaged tissue. Thus, anti-inflammatory drugs are often included in DESs to control chronic inflammation by reducing cytokine-driven neotintimal growth. Long-term administration of anti-inflammatory drugs, however, can shut down the healing process completely.
While generally effective, current DESs have not completely served certain subsets of patients. For example, in the SIRIUS clinical trial, patients with diabetes were roughly twice as likely as non-diabetics to incur binary restenosis. Further, diabetic patients tend to generally be more prone, post PCTA and stent placement, to target lesion revascularization (TLR) and to major adverse cardiac events (MACE). It has been observed that increased MACE such as acute myocardial infarction (AMI), thrombosis and cardiac death in diabetics during approximately the first year post stent placement correlate well with target lesion revascularization (TLR). TLR, in turn, correlates well with the presence of restenosis in or near a target lesion.
What is needed is a method of treating vascular disease in diabetics that addresses the increased risk of MACE both simply by virtue of the presence of diabetes and that associated with TLR. This invention provides such a method.